This proposal aims to identify and characterize novel gene variants conferring susceptibility to suicidal behavior. We will do this both through intensive follow-up of a strongly implicated chromosomal region, and through performing the first ever exome-wide search for rare variants related to this phenotype. While suicidality is perhaps the most dreaded aspect of psychiatric disorders, relatively little research has been devoted to its biological basis. Yet family, twin, and adoption studies make clear that suicidal behavior has a substantial heritable component. While there is evidence that this heritability is accounted for in part by a liability to mood disorder, other evidence suggests an independent heritable facet that may cut across multiple psychiatric disorders. This independent feature has been hypothesized to be a liability to aggressiveness and impulsivity, the genetic study of which has focused on serotonergic genes. However, little systematic genetic investigation of the suicidality phenotype has been undertaken. In the first iteration of this grant, we conducted an attempted suicide genome-wide association study (GWAS), which generated an association signal on 2p25 at rs300774 (p=5.07 X 10-8), a finding that is on the threshold of genome-wide significance (p<5X10-8). The associated SNPs on 2p25 fall in a large linkage disequilibrium block that contains the ACP1 gene, whose expression is significantly elevated in bipolar disorder (BP) subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that interacts with beta-catenin. The connection to beta-catenin, a key molecule in the Wnt signaling pathway, is noteworthy because the Wnt pathway is positively regulated by lithium, which has been shown to decrease suicidal behavior. The connection between suicidal behavior and beta-catenin was further supported by our gene set enrichment analysis of our attempted suicide GWAS dataset and by our initial whole-exome sequencing of 39 BP attempters and 60 BP non- attempters. We propose to follow up these findings by resequencing the 2p25 candidate region and by conducting a secondary analysis of whole-exome data from 800 attempters and 1,200 non-attempters, allowing us to search for functional variants influencing the risk for suicidal behavior on 2p25, in Wnt-related genes, and throughout the genome. To accomplish this, we will employ the diverse and complementary skill sets of an outstanding team of investigators including experts in molecular genetics, statistical genetics, bioinformatics, neurobiology, and psychopathology. The identification of candidate genes and functional variants associated with suicidal behavior would have a significant public health impact because it would provide new insights into the biological basis of suicidal behavior, provide new therapeutic targets, and provide the data needed to generate in vivo models in which to test therapeutic targets. PUBLIC HEALTH RELEVANCE: Suicidal behavior is perhaps the most dreaded aspect of psychiatric disorders and among the leading causes of death for young people. This proposal aims to identify genetic factors that increase the risk for suicidal behavior.